1. Field of the Invention
The invention relates generally to methods for treating bacterial infections by inhibition of L,D-transpeptidases and more specifically to methods for treating tuberculosis by inhibiting a Mycobacterium tuberculosis L,D-transpeptidase.
2. Background Information
Tuberculosis (TB) continues to be a major public health threat around the world The estimate that more lives will be lost in 2009 due to TB than in any year in history is alarming. An increasing number of cases reporting infection with multi-(MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis has diminished our capability to respond effectively against this threat. A recent study reporting high mortality rates of patients co-infected with HIV and XDR-TB illustrates the need for new drugs to treat TB. It is speculated that poor patient compliance to treatment regimen, as the current therapy requires a combination of drugs to be taken daily for 6 months or more, is a major reason for emergence of drug resistance in TB. While >99% of M. tuberculosis bacilli are killed within 2 weeks of therapy, it takes the remainder of the therapy to effectively kill the surviving population. These bacilli, broadly termed ‘persisters’, are able to transiently tolerate drugs. The phenomenon of persistence is poorly understood. In vitro models designed to mimic the physiology of persisters are based on exposure to nitric oxide and depletion of oxygen and nutrients as these conditions are thought to prevail in a persisting infection in vivo.
A higher percentage of bacilli are able to survive exposure to drugs at stationary phase compared to exponential phase of growth. The bacterial cell wall, as an interface between the pathogen and the host, regulates diffusion, influx and efflux of drugs and metabolites. Integrity and permeability of this interface is highly significant to effective targeting of M. tuberculosis with drugs. Little is known about changes in the cell wall during chronic phase of infection and whether it regulates persistence of M. tuberculosis in the host. The mechanism by which M. tuberculosis maintains 3→3 cross-linkages in the peptidoglycan layer is poorly understood. An understanding of the factors involved in the regulation of cell wall physiology is crucial for developing drugs that effectively target and kill the persisters by interfering with this process.